What is serum protein electrophoresis (SPEP) used for when evaluating peripheral neuropathy before initiating gabapentin, pregabalin, duloxetine, or rosuvastatin?

Serum Protein Electrophoresis in Peripheral Neuropathy Evaluation

Serum protein electrophoresis (SPEP) is used to detect monoclonal gammopathies that can cause peripheral neuropathy, but immunofixation electrophoresis (IFE) should be ordered instead as it is significantly more sensitive and is the recommended test for evaluating peripheral neuropathy before initiating symptomatic treatments like gabapentin, pregabalin, or duloxetine. 1, 2

Why SPEP/IFE Testing Matters

The primary purpose is to identify treatable causes of neuropathy that require disease-modifying therapy rather than just symptomatic management. 1 Approximately 10% of patients with peripheral neuropathy of unknown cause have a monoclonal gammopathy, which is substantially higher than the general population. 1, 3 Missing these diagnoses can have devastating consequences, as some represent underlying malignancies requiring specific treatment. 4

Critical Diagnostic Advantage of IFE Over SPEP

• IFE detects approximately 17-30% of monoclonal gammopathies that SPEP misses, particularly small or non-malignant monoclonal proteins. 1, 2
• Relying solely on SPEP without IFE results in missed diagnoses in nearly one in five patients with paraproteinemic neuropathy. 4
• The American Academy of Physical Medicine and Rehabilitation specifically recommends serum protein immunofixation electrophoresis (IFE), not SPEP alone, as it has the highest yield of abnormality in determining the cause of distal symmetric polyneuropathy. 1

Conditions Detected That Change Management

IgM Monoclonal Gammopathies

• Waldenström's macroglobulinemia, which affects up to 22% of patients with paraprotein-related peripheral neuropathy and requires chemotherapy rather than symptomatic treatment alone. 5
• IgM antibodies against myelin-associated glycoprotein (anti-MAG), found in approximately 50% of patients with demyelinating symmetric sensory peripheral neuropathy. 2
• Associated conditions include autoantibody activity, type I or II cryoglobulinemia, macroglobulinemia, or chronic lymphocytic leukemia. 1

IgG or IgA Monoclonal Gammopathies

• Multiple myeloma, which requires oncologic treatment. 2
• AL amyloidosis, one of the most frequently missed diagnoses that can cause peripheral neuropathy with autonomic features. 2, 4
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), which is often misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). 4
• Monoclonal gammopathy of undetermined significance (MGUS), which requires monitoring as lymphoproliferative malignancy may develop after many years. 6

Clinical Context for Testing

Before initiating symptomatic treatments (gabapentin, pregabalin, duloxetine) for peripheral neuropathy, IFE must be performed to rule out paraproteinemic causes that require disease-specific therapy. 5 In Waldenström's macroglobulinemia, for example, gabapentin, pregabalin, and duloxetine are used only as adjunctive symptomatic treatments while the patient undergoes plasmapheresis or chemotherapy to reduce IgM levels—not as primary therapy. 5

Treatment Implications When Paraprotein is Found

• Patients achieving a major response (≥50% reduction in serum IgM) have significantly better symptomatic improvement (79% vs. 35.5%, P < .0001) compared to those without paraprotein reduction. 5
• This means symptomatic medications alone are inadequate if an underlying paraproteinemic cause is present and untreated. 5

Recommended Testing Algorithm

Initial Laboratory Workup for Peripheral Neuropathy

1. Blood glucose (fasting blood glucose and/or hemoglobin A1c) to screen for diabetes mellitus, the most common cause. 1, 7, 8
2. Serum B12 with metabolites (methylmalonic acid with or without homocysteine) to identify vitamin B12 deficiency. 1, 7, 8
3. Serum protein immunofixation electrophoresis (IFE) to evaluate for monoclonal gammopathy. 1, 2, 7, 8

Additional Testing When IFE is Positive

• If IgM paraprotein is detected, test for anti-myelin-associated glycoprotein (anti-MAG) antibodies. 1
• Collaborate with hematology to determine whether findings represent MGUS, AL amyloidosis, multiple myeloma, or Waldenström's macroglobulinemia. 2
• Consider serum free light chains if SPEP/IFE are normal but clinical suspicion remains high, as this may reduce misdiagnosis rates. 4

Critical Pitfalls to Avoid

• Ordering SPEP alone without IFE misses approximately 17-30% of monoclonal gammopathies. 1, 2
• Approximately 25% of patients with paraproteinemic neuropathy had not been screened with SPEP or IFE prior to referral to tertiary centers. 4
• Dismissing a detected monoclonal protein as "just MGUS" without proper hematologic evaluation leads to missed diagnoses of AL amyloid and POEMS syndrome. 4
• Initiating symptomatic treatment with gabapentin, pregabalin, or duloxetine without first ruling out treatable causes delays appropriate disease-modifying therapy and worsens outcomes. 5, 4
• Failing to monitor patients with MGUS-associated neuropathy, as lymphoproliferative malignancy may develop years later. 6